The overall goal of this research is to test the feasibility of identifying and characterizing brain parenchymal disease invisible to conventional MRI that differentiates secondary-progressive (SP) from relapsing-remitting (RR) multiple sclerosis (MS) patients using diffusion and MT MRI and MRS. We will: Aim 1. Quantify structural brain parenchymal disease burden in the normal-appearing white matter for relapsing-remitting (RR) and secondary-progressive (SP) multiple sclerosis (MS) patients using quantitative whole-brain diffusion MRI and magnetization transfer (MT) MRI. We will test the hypothesis that SPMS patients harbor disease in normal-appearing white matter that is characterized by quantitatively abnormal diffusion and MT, as defined by normal controls, whereas RRMS patients have abnormal normal-appearing white matter on MT but may retain normal diffusion by histogram analysis. Aim 2. Characterize differences in whole-brain disease in normal-appearing white matter of RRMS and SPMS patients, as shown by diffusion and MT histogram analysis, using metabolite maps and quantitative metabolite analysis by whole-brain MR spectroscopy (MRS). Since axonal loss is thought to represent the histopathologic indicator of irreversible disease and the cause of morbidity in MS, we predict that total cerebral N-acetyl aspartate (NAA), the putative neuronal marker, will be abnormal in the normal-appearing white matter of MS patients with irreversible disease. We will test the hypotheses that: a) clinical disability correlates to NAA levels only in those patients with abnormal diffusion. This study will exploit new MR pulse sequences in a combined approach and apply them quantitatively to evaluate total brain normal-appearing white matter, in isolation, in MS patients. The future extension of this exploratory work will be a large scale, longitudinal study in which we will test that abnormalities in normal-appearing white matter on diffusion MR in RRMS predict progression to SPMS, and perfusion changes.